PF-4136309

PF-4136309 is a potent, selective, and orally bioavailable CCR2 antagonist, with IC₅₀s of 5.2 nM, 17 nM and 13 nM for human, mouse and rat CCR2. IC50 & Target:IC50: 5.2 nM (Human CCR2), 17 nM (Mouse CCR2), 13 nM (Rat CCR2)^[1] In Vitro: PF-4136309 is potent in human chemotaxis activity (IC₅₀=3.9 nM) and in the whole blood assay (IC₅₀=19 nM), with IC₅₀ of 16 and 2.8 nM in mouse and rat chemotaxis assays. PF-4136309 is potent in inhibiting CCR2 mediated signaling events such as intracellular calcium mobilization and ERK (extracellular signal-regulated kinase) phosphorylation with IC₅₀ values of 3.3 and 0.5 nM, respectively. In hERG patch clamp assay, PF-4136309 inhibits hERG potassium current with an IC₅₀ of 20 μM. PF-4136309 is not a cytochrome P450 (CYP) inhibitor, with IC₅₀ values of >30 μM against five major CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Moreover, PF-4136309 is not a CYP inducer at concentrations up to 30 μM^[1]. In Vivo: PF-4136309 (2 mg/kg) exhibits a moderate half-life in both species after iv administration (2.5 and 2.4 h). When administered orally, PF-4136309 (10 mg/kg) is absorbed rapidly, with peak concentration time (T_max) at 1.2 h for rats and 0.25 h for dogs. A similar half-life is observed in both species between iv dosing and po dosing. PF-4136309 is well absorbed, with an oral bioavailability of 78% in both species^[1].